IPB's Sheng Cui Research Team Solves the First Structure of the MERS-CoV nsp13 Helicase


The Sheng Cui Research Team of the Institute of Pathogen Biology (IPB) under the Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS&PUMC) has solved the crystal structure of the full-length 3.0Å-resolutoin MERS-CoV nsp13 helicase. It is the first nsp13 helicase structure of corona virus (CoV). CoV helicase is not only one of the most conserved evolutionary nonstructural proteins (nsps) but aslo one of core proteins that constitute viral transcription/replication transcription complex. CoV helicase is a multi-structural domain protein with large conformational change and extremely high structure-solving difficulties. Since the outbreak of SARS in 2003, many laboratories attempted to solve its structure but none of them has succeeded. Sheng Cui and his research team, after making persistent efforts and attempting nearly all CoV helicases, has finally solved the crystal structure of MERS-CoV nsp13. The contribution of their work to research on corona virus can be seen from the Reviewer’s comment.

The research results were published in an online article titled “Crystal Structure of Middle East Respiratory Syndrome Coronavirus Helicase” in Plos Pathogens on June 27, 2017.

Link of the original text: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006474




Figure 1. Three-dimensional structure and composition of structure domain of MERS-CoV nsp13 full-length protein


The global SARS (severe acute respiratory syndrome) and MERS (Middle Eastrespiratory syndrome coronavirus) epidemics caused by corona virus broke out and remain a threat to public health; however, effective vaccine or drug against CoVs remains unavailable. CoV helicase is one of the most conserved evolutionary nonstructural proteins (nsps), and one of core proteins that constitute viral transcription/replication transcription complex, thus making it an important target for drug development. Nsp13 belongs to SF1 helicase super family and has several enzymatic activities, including hydrolysis of NTPs and dNTPs, unwinding of DNA and RNA duplexes with 5’-3’directionality and the RNA5’-triphosphatase activity. Through resolution of crystal structure, the researchers have found that, MERS-CoV nsp13 has multiple domains, including an N-terminal Cys/His rich domain (CH) with three zinc atoms, a beta-barrel domain and a C-terminal SF1 helicase core with two RecA-like subdomains. Compared with existing protein structure databases, we have found that, on one hand, the overall domain organization structure of nsp13 is similar to that of EAV nsp10, indicating that the structure of helicase is highly conserved in nidovirales; on the other hand, the structure of all structure domains in nsp13 is more similar to the structure domain corresponding to the Upf1 helicase in eucaryotic organism. That is to say, if Upf1 is considered as an advanced version in the evolution of Upf1-like helicase, EAV nsp10 can be seen as simple version, while CoV nsp13 is between Upf1 and EAV nsp10 inevolution. It is worth noting that, the N-terminal CH structure domain of CoV nsp13 highly resembles CH of Upf1. Upf1 takes part in nonsense-mediated mRNA decay (NMD), and NMD can recognize and degrade exogenous RNA (including viral RNA), and cause the host defense mechanism. Therefore, nsp13 may take part in quality control of viral RNAs synthesis, and can support the efficient replication of its exceptional RNA large genome; nsp13 may also use the CH structure domain that is highly similar to Upf1 to disturb the host NMD, thereby resisting the NMD-mediated anti-viral mechanism. The assumptions need further experimental evidences.




Figure 2 Structures of MERS nsp13, EAV nsp10 and Upf1


(Institute of Pathogen Biology)